NM_032119.4:c.18754G>A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_032119.4(ADGRV1):c.18754G>A(p.Asp6252Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000298 in 1,611,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_032119.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000114 AC: 28AN: 246360Hom.: 0 AF XY: 0.000127 AC XY: 17AN XY: 133636
GnomAD4 exome AF: 0.000313 AC: 457AN: 1459644Hom.: 0 Cov.: 32 AF XY: 0.000306 AC XY: 222AN XY: 725974
GnomAD4 genome AF: 0.000158 AC: 24AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
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Identified in a patient with autism in published literature; has not been published in association with an ADGRV1-related disorder to our knowledge (PMID: 35982159); In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 35982159) -
The p.Asp6252Asn variant (rs201800819) has not been reported in the medical literature, is absent from ClinVar, and has not been previously identified in our laboratory. The p.Asp6252Asn variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.011% (identified in 31 out of 274,368 chromosomes). The aspartic acid at codon 6,252 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses suggest that this variant does affect the structure/function of the ADGRV1 protein (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Asp6252Asn variant cannot be determined with certainty. -
not specified Uncertain:1
The p.Asp6252Asn variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome. This variant has been identified in seve ral populations by the Exome Aggregation Consortium, including 8/61548 European chromosomes (ExAC, http://exac.broadinstitute.org; dbSNP rs201800819); however, its frequency is not high enough to rule out a pathogenic role. Computational pr ediction tools and conservation analyses do not provide strong support for or ag ainst an impact to the protein. In summary, the clinical significance of this v ariant is uncertain. -
Inborn genetic diseases Uncertain:1
The c.18754G>A (p.D6252N) alteration is located in exon 89 (coding exon 89) of the ADGRV1 gene. This alteration results from a G to A substitution at nucleotide position 18754, causing the aspartic acid (D) at amino acid position 6252 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Usher syndrome type 2C Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
ADGRV1-related disorder Uncertain:1
The ADGRV1 c.18754G>A variant is predicted to result in the amino acid substitution p.Asp6252Asn. To our knowledge, this variant has not been previously reported in association with retinal disease; however, this variant was identified in one individual in a large cohort of individuals with autism (supplementary data, Zhou et al. 2022. PubMed ID: 35982159). This variant is reported in 0.021% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at